Robert L. Coleman, MD, FACOG, FACS, discusses the VELIA trial and the impact the results are going to have on the use of PARP inhibitors in ovarian cancer.
Robert L. Coleman, MD, FACOG, FACS
Data from the phase III VELIA trial demonstrated that the frontline combination of veliparib, carboplatin, and paclitaxel followed by maintenance veliparib is a viable treatment strategy for women with high-grade serous ovarian cancer, particularly those with BRCA1/2 mutations, according to lead study author Robert L. Coleman, MD, FACOG, FACS.
In the trial, patients were randomized to 1 of 3 arms: carboplatin and paclitaxel plus placebo followed by placebo maintenance, veliparib plus carboplatin and paclitaxel followed by veliparib maintenance, or veliparib plus carboplatin and paclitaxel followed by placebo maintenance.
Findings from the first 2 arms of the trial were presented at the 2019 ESMO Congress. Among the entire study population, the median progression-free survival (PFS) was 23.5 months in the veliparib induction/maintenance arm versus 17.3 months in the placebo arm (HR, 0.68; 95% CI, 0.56-0.83; P <.001). Among patients who harbored BRCA1/2 mutations, the median PFS was 34.7 months versus 22.0 months with veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28-0.68; P <.001).
Patients with homologous recombination deficiency (HRD) also derived benefit from the addition of veliparib to induction and maintenance therapy, albeit to a lesser extent. Among this population, the median PFS was 31.9 months versus 20.5 months in the combined veliparib and placebo arms, respectively (HR, 0.57; 95% CI, 0.43-0.76; P <.001).
Regarding safety, grade 3/4 adverse events (AEs) were reported in 88% of patients who received veliparib upfront and as maintenance, 88% of patients who received veliparib only in the induction combination, and in 77% of patients who received placebo throughout.
“The results are going to impact the way physicians look at the treatment strategies they have planned for patients,” said Coleman. “If they're planning on using a neoadjuvant approach, or a chemotherapy-alone approach, [they may want to consider adding veliparib] now that we know that it can benefit patients.”
In an interview with OncLive, Coleman, professor and Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, discussed the VELIA trial and the impact the results are going to have on the use of PARP inhibitors in ovarian cancer.
OncLive: Could you provide the rationale for the VELIA trial?
Coleman: We believe PARP inhibitors could augment chemotherapy. As such, we evaluated the efficacy of the PARP inhibitor veliparib in combination with chemotherapy [as upfront therapy] and as maintenance therapy. [VELIA] was set up as a 3-arm trial. The control arm consisted of paclitaxel and carboplatin plus placebo, followed by placebo maintenance, while the experimental arm consisted of paclitaxel, carboplatin, and veliparib, followed by veliparib maintenance. The third arm of the trial looked at the combination of paclitaxel, carboplatin, and veliparib, followed by placebo maintenance.
What sets veliparib apart from other PARP inhibitors?
PARP inhibitors have been evaluated in ovarian cancer since they were discovered to have preclinical efficacy in BRCA1/2-deficient tumors. Veliparib [has a] unique mechanism of action. There are 2 primary mechanisms of PARP: one is the catalytic engagement of PARP itself, and the second is that it can trap PARP onto the DNA. We believe that veliparib may be a relatively weak PARP trapper. As such, we can co-administer it with chemotherapy with cytotoxic intent. Veliparib is one of the very few PARP inhibitors that can be given with full-dose chemotherapy.
In the trial, we planned for carboplatin to be given at an area under the curve of 6 and the paclitaxel regimen at 80 mg/m2 weekly, or at 175 mg/m2 every 3 weeks. We planned for full-dose chemotherapy. When we added the PARP inhibitor, which was given at a reduced dose, we were able to maintain the carboplatin dose intensity at about 80% to 85% among all 3 arms, the weekly paclitaxel strategy at about 80%, and the every-3-week strategy at about 90%. We were completely within the target zone for these drug doses given in combination with a PARP inhibitor.
Could you discuss the findings that were presented at the 2019 ESMO Congress?
We compared the combination of veliparib plus chemotherapy followed by veliparib maintenance with the control arm. The primary endpoint of this particular analysis was PFS. We looked at the efficacy of this combination in 3 distinct populations. The first population included about 200 patients with a germline or somatic BRCA1/2 mutation. The second group included patients with HRD, and this included those 200 patients with a BRCA1/2 mutation. Then, we added the patients who had BRCA1/2 wild-type disease but [also] had HRD, and that was about 421 patients total. The third group included the entire patient population of 757 patients.
In each cohort, the addition of veliparib improved PFS significantly. The effect was the strongest in the BRCA1/2 population, as we expected. The reduction in the risk of progression or death was about 56%. The risk reduction was 43% in the HRD population and 32% in the overall population. We are very excited to see that the addition of veliparib to chemotherapy was active across all the patient populations we were studying.
What’s unique about this study is that we randomized patients [to treatment] at the beginning of their chemotherapy. All the other trials that have been done to date, including SOLO-1, PAOLA-1, and PRIMA, only looked at PARP inhibitors in the [frontline] maintenance setting. Patients were defined by their response to induction therapy. What's different about this trial is that we did not make that assumption. We included all-comers and calculated PFS from that point on.
Could you discuss the safety profile of the regimen?
PARP inhibitors have been associated with some unique class adverse events, such as nausea, vomiting, and taste changes, and we did see those symptoms to some extent. However, we didn’t see increased toxicity in patients who received chemotherapy. Interestingly, we didn't see an augmentation of the myelosuppressive toxicity that we see with chemotherapy.
How will these findings impact current practice?
We will have to follow the eligibility criteria of the trial if we want to see similar outcomes. This trial gives us confidence that we can add veliparib to [chemotherapy] in patients with a germline or somatic BRCA1/2 mutation at diagnosis. In the BRCA1/2-positive population and the non-BRCA1/2—mutant populations, we still saw a benefit with veliparib combined with chemotherapy and as maintenance therapy.
How could these findings impact the use of other PARP inhibitors?
The way veliparib is going to impact the other PARP inhibitors has to do with our understanding of what happens when a patient has been previously exposed to a PARP inhibitor. Essentially all of the trials that have been done to date [that resulted in FDA approvals] were done in patients who had never been exposed to PARP before.
With this trial, and our experience with olaparib (Lynparza) and niraparib (Zejula), we are seeing earlier exposure to PARP inhibition in a large proportion of patients who had received a PARP inhibitor before. [Our findings] may not impact the other PARP inhibitors so much, but [the indications] in which the other PARP inhibitors are already approved. Ultimately, it's good to have these agents in the public domain so that we can use them. However, [we don’t know] how this will affect the treatment paradigm for patients who recur and have had prior exposure to PARP.
Where will future research efforts be focused?
The world of prior PARP exposure is evolving rapidly. We're very interested in looking at these drugs in combination with antiangiogenic inhibitors and immune checkpoint inhibitors. Because of veliparib’s unique qualities, we have the opportunity to look at these combinations in the recurrent setting. The optimal role of veliparib is still [being determined]. Because of the earlier exposure to these agents, the field is going to move in a direction where we look at how to augment the efficacy of these drugs with combinations, [find ways to] overcome adaptive resistance, and find combinations [that broaden the efficacy of PARP to populations we wouldn’t otherwise expect]. There’s a lot of work to be done.